Steroid compounds



Patented Mar. 2, 1954 2,671,093 STEROID COMPOUNDS Frank H. Lincoln, Jr.,and George B. Spero, Kalamazoo, Mich., assignors to The Upjohn Company,Kalamazoo, Mich., a corporation of Michigan No Drawing. ApplicationSerial No.

17 Claims. (01. 260397.45)

may be represented by the formula:

(1311: o=o I -OH R-o-- HO J wherein R, is selected from the groupconsisting of hydrogen and the acyl radical of an organic carboxylicacid, especially those containing from one to eight carbon atoms,inclusive. The configuration of the 3-hydroxy group in the above formulaand elsewhere in this application includes both alpha and beta formsunless otherwise specified, and the configuration of the 17- hydroxygroup in the above formula and elsewhere in this application is alpha.

It is an object of the present invention to provide a group of novelcompounds, Ila-oxygenated- 3,17 dihydroxypregnane 20 ones, which haveutility in the preparation of biologically-active compounds, such ascortisone and its derivatives, and which are also physiologically activeper se. A further object of the invention is the provision of a processfor the production of certain Ila-oxygenated-'i,1'7-dihydroxypregnane-20-ones. Other objects of the invention will beapparent to those skilled inthe art to which this invention pertains.

February 14, 1952, 271,636

The compounds of the present invention, 11-oxygenated-3,17-dihydroxypregnane-20-0nes, are useful in the preparationof other steroid compounds having an oxygen atom at carbon atom eleven,such as cortisone acetate, which may bev obtained from the compounds ofthe present invention by known methods, for example, by hydrolysis ofthe eleven-acyloxy group, if present, to an eleven-hydroxy group usingacid or base, bromination with bromine in chloroform to introduce abromine atom at the 21 position, oxida tion of the three andeleven-hydroxy groups to ketone groups using chromic oxide, replacementof the 21-bromide by a 21-acetoxy group using potassium acetate inacetic acid, bromination with bromine in acetic acid to introduce abromine atom at the four position, treatment with semicarbazide tointroduce a double bond at the four position by removal of hydrogenbromide, the semicarbazone of the three-ketone group also being formedin this step, and hydrolysis of the semicarbazone with pyruvic acid toregenerate the three ketone. Such compounds are of particular interestin the field of steroid research due to the biological activity of thecortical hormones and certain known derivatives thereof. The importanceof such investigation is moreover emphasized by the shortage of adrenalcortical hormones, and the absence of any present suggestion for thealleviation of said shortage except through organic synthesis.

The 1la-oxygenated-3,17-dihydroxypregnane- ZO-ones which are ofparticular interest are those compounds of the above generic formulawherein R0 represents an eleven-hydroxy group and an ester of theeleven-hydroxy group with an organic carboxylic acid containing up toand including eight carbon atoms. Among such acids are formic, acetic,propionic, butyric, valeric, hexanoic, heptanoic, octanoic,cyclopentanoic, cyclopentylpropionic, benzoic, toluic, and the like.Preferred are those ester groups derived from the lower-aliphatic acids,especially those containing from one to eight carbon atoms, inclusive.The acids may also contain substituents, such as halo, alkyl, andmethoxy, which are non-reactive under the reaction conditions employed.The elevenester group of an 11a-oxygenated-3,l7-dihydroxy- 5pregnane-ZO-one is unchanged from the elevenester group present in thestarting compound.

According to the process of the present invenvention, 11a oxygenated3,17 dihydroxypregnane-ZO-ones of the above structural formulacontaining from one to eight carbon atoms, in- 15 elusive, by a reactionin which starting 17(20)- oxido-3,1111,20-triacyloxypregnanes, insolution in an organicsolvent which is non-reactiveunder the conditionsof thbreaction, are treated with a saponifying agent, to produce thedesired 11a- 20 oxygenated-3,17dihydroxypregnane-20-ones.

In carrying out the process of the present invention, a starting17(20)-oxido-3,11a,20triacyl oxypregnane is dissolved in an--organicsolvent which is substantially non-reactive undr-the' conditions of thereactiongsuch: as=methanol,v ethanol, acetone, or dioxane, or benzene ortoluene if a two-phase system is employed, or others, with ethanol beingpreferred. The resultingfsoa with an organic solvent, such aschloroform, washing the extract with various solutions, such as aqueoussodium chloride, drying the Washed extract with a drying agent, such asanhydrous sodium sulfate, removing the drying agent by filtration, andevaporating the organic solvent. The residue obtained after removal ofthe solvent may be purified, and separated into components if hydrolysishas been incomplete, by conven tional procedures, such aschromatographic adsorption, fractional crystallization, or the like.Sometimes it is preferred not to purify the prodnot since the residueobtained after removal of the washed and dried extraction solvent is ofsufficient purity to be used in subsequent reactions.

The starting compounds, as mentioned above, are the-117mm.- oxido3,-1la;20- triacyloxypregnaneswherein each acyloxyigro'uplis' an esterof a steroid hydroxy group with an organic carboxylic acid, especiallysuch acids containing up to and including eight carbon atoms. Amongsuch--aoids'*-are formic, acetic, propionic, butyric, valericrhexanoia.heptanoic, octanoic, cyclopen- 'ta-noic', cyclopentylpropionic, benzoic,toluic, and the'like, Preferredare those ester groups derived from thelower aliphatic acids, especially those containing from one. to eightcarbon atoms, inclusive; The'acids may also contain substituents,

lution is then admixed with an aqueous solution 'such as halo, alkyl,and methoxy, which are nonof a saponifying agent, such as scdium' orpotas-'- sium hydroxide, sodium or potassium carbonate, sodiumnorpotassium.bicarbonate, onother basic saponifying,agent, with sodiumhydroxide being preferred, agent required completely to hydrolyze thestarting- 1'? (20) oxido 3,110.,20 triacyloxypregnane; four to .twentygram equivalent weights, or even lessor -more,.of thesaponifyingagenttoone mole of-thestartingmateriahthe preferred ratio beingAO about: tentoone, yields a 3,1la,1l-trihydrox pregnane-QO-one. Use of the-:exactamount, oreven ;less,.of the saponifying agent required completely ,-tohydrolyze =-the starting 17 20) -oxido-- 3,-11a,20-triacyloxypregnanegives products -from i which both a 3,110,17-trihydroxypregnane-20= oneand an .1la acyloxy-3,1'7-dihydroxypregnane- 20-onemaybe-isolated; Theorder of= admixing of :thesteroidsolutionand and the aqueous solutionci=-thessaponifying'iagent isnot significant, k

although ordinarily; the aqueous saponifyingw solutionris-added tothestarting steroiddissolved in an: .organic solvent. 1 The resultingmixture -is'-' then :permittedto stand f or about fifteen minutes toabout two hours, or evenlongergthe exact time depending: in part upon.the temperature, in part upon the starting 17 (20)--oxido'-3,lla,20triacyl oxypregnane employed, and-impart uporrwhether complete -or:partialv hydrolysiss is desired; A" longer itime is 5generall'y;preferred if I complete hydrolysiscis'. desired, and: arshorter :time isgenerallyispreierred :if .zinco'mplete hydrolysiszis; aide-a sired.Temperatures between aboutt izerovand'. aboutrlOGzdegreea' oreven:lower".or::higher, :may ber-xemployed; room:ztemperaturexbeirigentirely satisfactory?irumostlinstancess in. general a highertemperaturegives a more =rapid-and more complete 'hydrolysis, anda lowertemperature gives a slower and less complete hydrolysis The reactionmixture" may be "agitatedcontinuously,

as-,-'-fdr examplabyishaking with a rotaryshalt ing;device or otherconventional stirring or'agitationTmeans. After completionoi;"thedesiredreaction,.the product may, be isolated inlany convenie'ntmanner, such as, for example, extraction Use of Ian ..excess.orthe.saponifying 35 may be-difierent, depending.- on-Hthe' precursors; sincethe ester groups-pf the 17(20) oxido- 3,11a,20-triacyloxypregnanes areunchanged from those -inthe precursors. a

The starting-:1?(20) 0xido-3,1laztl-triacyloxypregnanes are prepared byan oxidation reaction in:-which- .an atom-pf oxygen is added' to the 17(20) -ethylenicrlinkage a i5,l1;20 -tr-iacyloxy 17(20) -pregnene. Anyoxidant or epoxidizing agent capable of furnishing the necessary oxygenmay be employed. The agents most commonly used are hydrogen' peroxideand organic peracids, for examplexperacetic, perpropionic, perbutyric,perbenzoic, or chloroperacti'c; The reaction is carried out by mixing:together the intermediate 3,1la,20-triacyloxy 'l7(20) pregnene and theperacid of choice, preferably peracetic acid, or hydrogen peroxide for asuitable period, e, g., from about one-half to twentyefour hours"; thelength of time depending .upon theconcentration of oxygenfurnishin'giagenti' When" the oxidant is hydrogenperoxide,"glacialacetic acid 'is a convenientreaction medium: Whenaperacid' is employed any 'of the customary organic solvents in which"the' starting steroid is soluble can be used,.' such as chloroform, carbontetrachloride, ethylene dichloride"; methylene chloride, mixtures ofether and chloroform, and others, with chloroform being prefer-red;It"is.'sometiines desirable to add to the. oxidizing im'edium'a smallquantity of an alkali'm'et' -l 'salt','such asjfor example, so-

diumacetate. Temperatures between about zero ing-,the-.chloroform,= andcrystallizing the residuefrom any organic solvent which is non-reactivewith the oxide. It is sometimes preferred'not to crystallize theproduct, since the residue obtained after removal of the solvent is ofsufficient purity to be used in subsequent reactions.

The 3,11a,20-triacyloxy-17(20) -pregnenes used to prepare the starting17(20)-0Xid0-3,11a,20- triacyloxypregnanes can be produced by variousprocedures. The 3a,11a,20 triacyloxy 17 (20) pregnenes are convenientlyprepared by heating 3a,11a dihydroxypregnane 20 one, a 11a.-acyloxy-3a-hydroxypregnane-20-one, or a 3a.,1ladiacyloxypregnane-20-one,all of which are prepared from progesterone as described below, with alarge excess of an organic carboxylic acid anhydride in the presence ofan acid catalyst such as sulfuric acid, sulfonic acids, or the like,with paratoluenesulfonic acid being preferred. The mixture is heated,usually at about 100 to 180 degrees centigrade, preferably at theboiling point, until the anhydride is nearly completely removed bydistillation, which may require a period of about four hours. The rateof distillation may be faster or slower, and any period of about twohours to eight hours or even shorter or longer is operative. If theanhydride used has a high boiling point or is a solid, a suitablesolvent such as toluene, xylene, paraffin hydrocarbons, or the like, maybe used to control the temperature. The preferred anhydride is aceticanhydride, but other anhydrides, such as propionic, butyric, valeric,hexanoic, heptanoic, and octanoic, anhydrides, as well as benzoic acidanhydride, ortho-toluic acid anhydride, and the like are also operative.The acid anhydrides can also be substituted with non-reactive groups,such as halo, alkyl, and methoxy, as in the case of chloroacetic,orthotoluic, or methoxybenzoic acid anhydrides. Under the conditions ofthe reaction, hydroxyl groups at carbon atoms three and eleven will beacylated.

The 311,1ladihydroxypregnane-20-0ne, the3,lla-diacyloxypregnane-20-ones, and the11aacyloxy-3a-hydroxypregnane-20-0nes are prepared from progesterone bythe following reac tions.

fully described in Preparation 1. The lla-h'ydroxyprogesterone isreduced with hydrogen in ethanol using a palladium-charcoal catalyst togive l1a-hydroxypregnane-3,20-dione. tion of the11a-hydroxypregnane-3,20-dione with sodium borohydride in dioxane givesthe desired 3a,l1a-dihydroxypregnane20-one. Acylation of thella-hydroxypregnane-3,20-dione with an acylating agent, for example, anacid anhydride, such as acetic anhydride, to give anlla-acyloxypregnane3,20-dione, followed by reduction of the11a-acyloxypregnane-3,20-dione with sodium bo rohydride in dioxane,gives the desired lie-acyloxy-3a-hydroxypregnane-20-ones. Subsequentacylation of an 11a-aoyIoXy-Ba-hydroxypregnane- 20-one with an acylatingagent, for example, an acid anhydride, such as acetic anhydride,produces the desired 3a, la-diacyIOXypregnane-ZO- ones.

3p,11a,20-triacyloxy-l7(20) -pregnenes may be prepared fromlla-acyloxy-3fl-hydroxypregnane- 20-ones in the same manner as'describedabove for the preparation of 311,11a,.20-triacyloxy-17- (20) -pregnenesfrom lla-acyloxy-3a-hydroxypregnane-20-ones. The11a-acyloxy-35-hydroxypregnane-20-ones are prepared by catalyticreduction of l1a-acyloxypregnane-3,20-diones, prepared from progesteroneas described above, using hydrogen and a Raney nickel catalyst.

Progesterone is oxidized to lla-hydroxyprogesterone by a fermentationprocess more Reducr process and products of the present invention, butare not to be construed as limiting.

PREPARATION 1.11a-HYDBOXYPROGESTERONE A medium was prepared from fivemilliliters of corn steep liquor, twenty grams of Edamine commerciallactalbumin digest, and fifty milligrams of Cerelose commercialdextrose, per liter of tap water and adjusted to a pH of between about5.5 and about 5.9. To four liters of this medium containing a 32 to 48hour growth, at room temperature with aeration, of Rhieopus arrhz'zus,was added one gram of progesterone in fifty milliliters of acetone. Theculture was then incubated at room temperature for 48 hours. At the endof this time the pH of the medium was 3.5 and the fermentation liquorand mycelia were extracted successively with three one-liter portions,one two-liter portion, and one one-liter portion of methylene chloride.The methylene chloride extracts were combined and washed with two 490-milliliter portions of two per cent aqueous sodium bicarbonate solutionand three EGO-milliliter portions of water. The methylene chlorideextract was evaporated to dryness in vacuo and the solids taken up infifty milliliters of methylene chloride. The solution was transferred toa -milliliter beaker and evaporated by a stream of air. The solids,weighing 1.585 grams, were dissolved in five milliliters of hot methanoland allowed to cool slowly at room temperature, whereupon 75 milligramsof crystals separated out. The mother liquor was freed of solvent byaeration, dissolved in fifty milliliters of benzene, and chromatographedover alumina (A1203). Fifty grams of acid-washed alumina, dried at 45degrees centigrade, was used as adsorbent and 100-milliliter portions ofsolvents were used to develop the column. The solvents and the orderused were as follows: benzene, benzene, benzene plus 5 per cent ether,benzene plus 5 per cent ether, benzene plus 10 per cent ether, benzeneplus 10 per cent ether, benzene plus 10 per cent ether, benzene plus 50per cent ether, benzene plus 50 per cent ether, ether, ether, ether plus5 per cent chloroform, ether plus 5 per cent chloroform, ether plus 10per cent chloroform, ether plus 10 per cent chloroform, ether plus 50per cent chloroform, ether plus 50 per cent chloroform, chloroform,chloroform, chloroform plus 5 per cent acetonachlcroform plus 5 per centacetone, chloroform plus 10 per cent acetone, chloroform plus 10 percent acetone, chloroform plus 50 per cent acetone, chloroform plus 50per cent acetone, acetone, acetone, acetone plus 5 per cent methanol,acetone plus 5 per cent methanol, acetone plus 10 per cent methanol,acetone plus 1) per cent meth anol, acetone plus 50 .per cent methanol,acetone plus 50 per cent methanol. The chloroform and chloroform plusfive per cent acetone eluates were combined, evaporated to dryness, andthe residue dissolved in two milliliters of hot methano] and filtered.After overnight refrigeration, 171 milligrams of crystallinella-hYdIOXYPlOgGS- terone, melting at 166 to 167 degrees centigrade, wasobtained. 7 A sample recrystallized from methanol gave the followingconstants: melting point, 166-467 degrees centigrade; plus 175.9 degrees(chloroform) AnaZysz's.-Per cent calculated for Czifisnihz C, 76.4; H,9.10. Found: C, 76.6; H, 8.92.- The structure of this product wasfurther established by its conversion, with chromic acid in acetic acid,to ll-ketoprogesterone. ,[Reich- PREPARATION2.-11a-11YnsoxYPBncNANE-3,20-13mm;

A solution of -250 milligrams of lla-hydroxyprogesterone fromPreparation l'in 100 milliliters of.=ethanol containing six .drops oftriethylamine was subjected to hydrogenation at room temperature under apressure of about ten pounds of hydrogen in the presence oflfimilligrams of a thirty per cent palladium-charcoal:catalyst in a-Parrapparatus. with an auxiliary mercury manometer. The time required for1thev hydrogenation was about twenty minutes. The-reaction mixture wasfiltered and the .solvent was evaporated to yield 265:mil1igrams of.material melting at 145-185 degrees centigrade. This product wasextracted withamixture of onemilliliter of ether and nine millilitersof. Skelly Solve B. On standing, the extract deposited eighty milligrams(-32 per of. l1al1ydroxypregnane-3,20-dioneas feathery needles. whichmelted at 35-90 degrees centigrade. Recrystallization irom a" mixture ofabout six drops: of ethyl acetate and five. milliliters of Skelly SolveB did. not change the melting point.

; AnaZysis.-.Per cent calculated for 0211-12203: C, 75.86; H, 9.70.Found: C; 76.13;H, 9.63.

PREPARATION 3.3d;lla-DIHYDRDXYPREGNANEQOONE To a solutionr 5.31 grams oflla-hydroxypregnane-3,20-dione of Preparation 2 in 130 milliliters ofperoxide-free dioxane maintained at fifty degrees centigrade; in a waterbath was added a solution of 195.5 milligrams of sodium borohydride(assay 84 per cent) in five milliliters PREPARATION4.-11a-AoE'r0XYPREcNANE-SZO-DIQNE A mixture of 70.5 milligrams ofIla-hYdIOXY- pregnane 3,20 dione from-Preparation 2, 0.8 milliliter ofacetic anhydride, and 0.7 milliliter of pyridine was allowed to standfor sixteen hours at room temperature and then poured into ice water.The precipitated product was isolated by filtration and dried. The yieldof Ila-acetoxypregnane 3,20 dione, melting at 1435-1465 degreescentigrade, was 67 milligrams (84 per cent). After one recrystallizationfrom ether- Skelly Solve B, the melting point was 150-151 degreescentigrade; '[al =plus 63 degrees (:0.803 in chloroform).

Analysis-Per cent calculated for Gael-134042 C, 73.76; H, 9.15. j'Found: C, 73.93; H, 9.32.

PREPARATION 5.-11amosroxwiiwnroroxreaaenssn- 200m:

'To a solution of 200 milligrams (0.534 millimole) ofl1a-acetoXypregnane-B,20-dione from Preparation 4 dissolvedinten-milliliters of peroxide-free dioxane at fiftydegrees oentigrade wasadded dropwise with stirring a solution of 6.9 milligrams (0.152millim'olebased on: pure reagent) of sodium borohydride '(assay 83.5.per cent) in one milliliter of water; Thamixture was-stirred atifiity.degrees, centigradeaforcne cent) 8 hour-aandmcidineda-hy":pouringintoifiityrzmilhliters ctr-water :containing hydrochloric acid. The; oilwhich.'firsteseparated. crystallized-on standing. .yilhe solid'was;collected, washed with watenauddried: under reduced pressure at fiftydegrees; centig-rade. "The yield of lla-acetoxy-3a-hydroxypregnane-20-one, melting at 122-136 degrees --c.entigrade,-was156: milligrams. :The crude: productwwas-dissolved in fifteenmilliliters of benzene. and chromatographed over 7.5 grams ofsacidwashed alumina whichhad been dried air-120: degrees centigrade. .Thecolumn was deyelopedi-with- :two; :fiiteemmilliliter portions'vof each'ofzthe, following. seventeen solvents: benzone, benzene .and ,5, 10 and50 per; cent ether, ethenaetherand 5,210, and-50' per; cent chloroform,chloroformggchloroform and 5, 10, and 50 per cent acetone; acetone and5,10, and 50 per cent methanol, andi methanol. The product appeared infractions; 12,- (ether and 5'per; cent chloroformr-through 22.(chloroiorm and 10 per cent acetone). Combination of these. fractionsand recrystallization". from, ethyl acetate-SkellySolve1B:gave"93"milligrams of product melting at 'l40-1'43degreescentigrade. Two further recrystallizationsi from zisopropylether gavepure lh-acietoxy-Ba-hydroxypregnane-20-one, melting at 146-148 degreescentigrade.

AnaZysia-e-Per cent calculatde. for. CzzHssO-i: (3,.73xi;11,9154.FoundizC, 73.8; H, 9.61.

PREPARATION 6.-3a,11a-I mo1rroxYraEcNAnn-20mm Using the proceduredescribedin Preparation 4, the 11aacetoxy3a-hydroxypregnane-ZO-one from-Preparation-- 5-. was esterified with acetic anhydride. inpyridineto'yield '3a,l1a'-diacetoxypregna-ne-20-one.

PREPARATION 7.-3'a.,11e,20-rRIAcEToxY-17 (20) PREGNENE PREPARATIONS.3a,11a,20-TRIACETOXY-17 20) PBEGNENE Using. the same-procedure; as inPreparation 7, 1.0 gram of-3a,l1a-diacetoxypregnane-20-one fromPreparation 6 was treatedwith 0.45 gram of. para-toluenesulfonic acidand milliliters of acetic. anhydride. The yield'of 3a.,11a,20-t1lacetoxy-l'l (.20) :-.pregnene was; 0.7 gram, melting at1200-210degrees'::centigrade. A sample recrystallized for analysis from acetone-hexaneandfrom alcoholmelted at 211-213 degrees centigrade; [11.1 minus-16degrees (chloroform).

' Analysis-Per cent calculated-forCid-14006:v C, 70.4; H, 8.75. Found:C, 70.5.; H, 8.79.

PREPARATION 51-3a,11m,20-'rniAcE'roXY-1'7 (20) PBEGNENE Usingthesameprocedure as in Preparation '7, 2.42 ;.;grams of1-1e-acetoxy-3m-hydroxypregnane-ZQ-one. from Preparation. 5 was .treatedPREPARATION 10.3a,11a,20-TR1PBOPIONOXY-17 20) PREGNENE Using theprocedure described in Preparation 7, 31,11a-dihydroxypregnane-20-onefrom Preparation 3 is converted to 311,1 1a,20-tripropionoxy- 17(20)-pregnene with propionic anhydride in the presence ofpara-toluenesulfonic acid.

PREPARATION 11.8a,11a.-1)IAcEToxY-20ricorioNoxr- 17 (20) -PREGNENE Usingthe procedure described in Preparation 8,3a,1la-diacetoxypregnane-20-one from Preparation 6 is converted to3a,11a-diacetoxy-20-propionoxy-17(20 )-pregnene with propionic anhydridein the presence of para-toluenesulfonic acid.

PREPARATION 12.3fi,11a,20-TRIA0ET0XY-17 20) PREGNENE Using the proceduredescribed in Preparation 9, 3 8-hydroxy-11a-acetoxypregnane-20-one(prepared by the reduction of the lla-acetoxypregnane-3,20-dione ofPreparation 4 with hydrogen at two to three atmospheres pressure inmethanol at room temperature using a Raney nickel catalyst), isconverted to 3 8,11a,20triacetoxy-17(20) pregnene with acetic anhydridein the presence of para-toluenesulfonic acid.

In the same manner as given above, other 311. (or '5),11a,20-triacyloxy-17 (20) -pregnenes are prepared, including 3/3,11a,20tripropionoxy 17 (20) pregnene; 31311:; diacetoxy-ZO-propionoxy-17 (20)-pregnene; 3a,20-dipropionoxy-1la acetoxy 17(20) noyloxy 17 (20)-pregnene; 3a,20 dioctanoyloxy- 11a. propionoxy 17(20) pregnene; 3abenzoyloxy 11a acetoxy 20 butyroyloxy 17(20)-pregnene;3a,11a-diacetoxy-20 benzoyloxy-17(20) pregnene; 3a,11a,20tributyroyloxy- 17(20) pregnene; 3a,11a',20 trivaleroyloxy 171120)pregnene; 3a,11a,20 trihexanoyloxy 17(20) pregnene; 3a,].1a,20--triheptanoyloxy 17(20)-pregnene; and 3a,11a,20-trioctanoyloxy- 17 (20)pregnene.

- PREPARATION 13.-17 (20)-oxmo-3 ,11a,20-

' TRIACETOXYPREGNANE One and one-half grams of 3a,11a,20 -triacetoxy-17(20)w-pregnene (from Preparation 7, 8 or'9) was dissolved in7.5 milliliters of chloroform, and the solution was cooled in an icebath to about five degrees centigrade. Three and three-tenthsmillilitersof commercial grade forty per cent peracetic acid solution in which 100milligrams of sodium acetate had been dissolved was added, and theresulting mixture was then shaken on a mechanical shaking machine forabout two hours at room temperature to complete the reaction. Themixture containing the crude product was diluted with methylene chlorideand then washed with several 25-milliliter portions of ice-cold five percent aqueous sodium hydroxide solution followed by 2 5- milliliterportions of water until the wash solution was neutral to pH test paper.The neutral solution was dried with anhydrous sodium sulfate and thenfiltered to .remove the drying agent. The white crystalline residueobtained onevaporating the solvent from .the clear, dry

The

fifty milliliters of solution melted at 210-213 degrees centigrade.

Recrystallization from a mixture of ethyl acetate and Skelly Solve Bgave fiuffy needles of 17(20) oxido-3a,11a,20-triacetoxypregnane,melting at 214-217 degrees centigrade.

Analysis-Per cent calculated for C27H40O1i C, 68.04; H, 8.46. Found: C,68.33; H, 8.62; C, 67.90; H, 8.38.

PREPARATION 14.17 (20) -OXIDO-3a,11a,20- TRIACETOXYPREGNANE One gram of3a,11a,20-triacetoxy-17(20)-pregnene (from Preparation 7, 8 or 9) wasdissolved in fifteen milliliters of benzene and five milliliters of atwo-molar solution of perbenzoic acid in benzene Was added. Afterstanding at room temperature for two hours to complete the reaction, thesolution was diluted with thirty milliliters of benzene. The crude17(20)-oxido- 3a,11a,20-triacetoxypregnane, melting at 211214 degreescentigrade, was obtained using the same procedure for isolation as inPreparation 13.

PREPARATION 15-17 (20) -oxIDo-3a,11a,20- TR-IPROPIONOXYPREGNANE Usingthe procedure described in Preparation 13, 311,11a,20-tripropionoxy-17(20) -pregnene from Preparation 10 is converted to 17(20)-oxido-3a,11a,20 tripropionoxypregnane by oxidation with peracetic acid in thepresence of sodium acetate.

PREPARATION 16.-3a,11a-D1A0ET0XY-17 (20 -oxIDo-20- PROlPIONOXYPREGNANEUsing the procedure described in Preparation 14,311,11a-diacet0xy20-pr0pion0Xy-17(20) -pregnene from Preparation 11 isconverted to 311,117:- diacetoxy 17(20) oxido 20 propionoxypreg nane byoxidation with perbenzoic acid.

PREPARATION 17.17 (20 -oXID0-3p,11a,20- TRIAOETOXYPREGNANE Using theprocedure described in Preparation 13, 33,11c,20-triacetoxy-17(20)-pregnene from Preparation 12 is converted to17(20)-oxido- 35,11a,20-triacetoxypregnane by oxidation with peraceticacid in the presence of sodium acetate.

PREPARATION 18.17 (20) -0XIDO-3,6,11a,20- TBIAOETOXYPREGNANE Using theprocedure described in Preparation 14, 3 3,11a,20-triacetoxy-17(20)-pregnene from Preparation 12 is converted to 17(20)-oxido313,11a,20-triacetoxypregnane by oxidation with perbenzoic acid.

acetoxy 17(20) oxidopregnane; 17(20) oxido-3o1111,20-tributyryloxypregnane; 17 (20) oxido-311,11a,20-trivaleryloxypregnane; 17 (20)oxido-371,11a,20-trihexanoyloxypregnane; 17(20) oxido 3a,11a,20triheptanoyloxypregnane; 17(20) oxido 3a,11 ,20 trioctanoyloxypregham;and the like.

egn a K girogq'u "gyep alfeqiogi and .the,,.,chlo1:o.f orm extractwashed, with twenty 51. jmffif y in 1 s1 0-, pelnqe -equeons-$Qdium.&h10ride .fiolutibnend gfifw t' ejisulfine q'l t was; add d withr withi y musosodi m 5111mm. 5211mm.- s'w Iihg11.'3" mi11i1itrsof 30.5no'r'riiel'elqqeops ingna'gentwasnzemoxged byifiltretiomendjhe sol:sodium hydroxide solution. After standi'rig e bventiwasoremoyediby'eyanolfatip .ugdeitreflu d room tempenafiture. forthirtyhminutes, .the solution pressune tQgiVeQQmiHigmmS ,of produch as"an was' extracted owithnhloroformand the chloro- 011.: The.oi1wasrjdisisglyed inethylacetete and .eggp rgpt ggvgg izhegwesgged ij:;h twe nr ,y per Skelly Solve B was; 'ddedhgfiiter; fitandinggfqr graphiccolumn peeked with ainety gram s of 71.96; H; 9.78. Found? C; 12.21; H,9.53; C,

one of "the tr 3?droxy-'coinpourid."

converted by treatment with an aqueous sodium hydroxide solution to anoily product which was separated into11a-acetoxy-3p,I'I-dihydroxypregnane-20-one and3,8,11a,l7-trihydroxypregnaner- 20-one, as confirmed by analytical data.The ratio was about one part of the acetoxy compound for every ten partsof the trihydroxy compound.

Analysis of 11a-acetoxy-3p,17-dihydroxyp1'egnane-20-one.Per centcalculated for C'zsHssOs: C, 70.37; H, 9.25. Found: C, 70.43; H, 9.19.

Analysis of 313,1111,17-trihydroxypregnane-20- one-Per cent calculatedfor C21H34O4: C, 71.96; H, 9.78. Found: C, 71.80; H, 9.82.

Example 6.--3,8,11a,17-trihydroxypregnane- 20-one Using the proceduredescribed in Example 2, an alcohol solution of 17(20)-oxido-3,3,11a,20-triacetoxypregnane (from Preparation 17 or 18) wasconverted to 35,11a,17-trihydroxypregnane-20- one by treatment with anaqueous sodium hydroxide solution. This product was identical with the3,8,11a,17 trihydroxypregnane 20 one obtained as described in Example 5.

In the same manner as given above, other 1111.- acyloxy-3a(or 18),17-dihydroxypregnane-20-ones are prepared, including35,17-dihydroxy-1hpropionoxypregnane 20 one; 3,8,1'7 dihydroxy-11a-octanoyloxypregnane-20-one; 11 a-butyryloxy-3a,17-dihydroxypregnane-20-one; 341,17dihydroxy-l1a-valeryloxypregnane-20-one; 3a,1'7- dihydroxy 11ahexanoyloxypregnane 20- one; 311,17-dihydroxy-1la-heptanoyloxypregnane-20 one; 3a,17 dihydroxy 11a octanoyloxypregnane-20-one; and the like,depending on the starting material employed.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. An 11a oxygenated 3,17 dihydroxypregnane-20-one of the formula:

(IJH: o=o

-H RO--- wherein R is selected from the group consisting of hydrogen andthe acyl radical of a hydrocarbon carboxylic acid containing from one toeight carbon atoms, inclusive.

2. An 11a-acy1oxy-3a,l'l-dihydroxypregnane- 20-one, wherein the acyloxygroup has the formula AcO, Ac being the acyl radical of a hydrocarboncarboxylic acid containing from one to eight carbon atoms, inclusive.

3. An 11aacyloxy-319,17-dihydroxypregnane 20-one, wherein the acyloxygroup has the formula AcO, Ac being the acyl radical of a hydrocarboncarboxylic acid containing from one to eight carbon atoms, inclusive.

4. 11a-acetoxy-3a,17 dihydroxypregnane 20- one.

5. 3,17-dihydroxy-11 propionoxypregnane- 20-one. I

6. 11a-acetoxy-3p,17 dihydroxypregnane 20- one.

7. 3a,11a,17-trihydroxypregnane-20 -one.

8. 35,11a,17-trihydroxypregnane-20-one.

9. A process for the production of a mixture of3,11a,17-trihydroxypregnane-20 -one and11aacyloxy-3,17-dihydroxypregnane-20-one, which includes: treating (1) a17(20)-0Xid03,11a,20- triacyloxypregnane, wherein the acyloxy groupshave the formula AcO, Ac being the acyl radical of an hydrocarboncarboxylic acid containing from one to eight carbon atoms, inclusive, insolutionin an organic solvent which is nonreactive under the conditionsof the reaction, with (2) a saponifying agent, to produce the desiredmixture.

10. A process for the production of an11aacyloxy-3a,17-dihydroxypregnane-20-one which includes: treating (1) a17(20)-OXid0-3a,11a,20- triacyloxypregnane, wherein the acyloxy groupshave the formula AcO, Ac being the acyl radical of an hydrocarboncarboxylic acid containing from one to eight carbon atoms, inclusive, insolution in an organic solvent which is non-reactive under theconditions of the reaction, with (2) a solution of an alkali metalhydroxide in amount not more than the theoretical amount requiredcompletely to hydrolyze the starting 17- (20)-oxido-8a,1111,20-triacyloxypregnane, and (3) separating thethus-produced 11a-acyloxy-3u,17- dihydroxypregnane-20-one from thereaction product.

11. A process for the production of an 11::-acy1oxy-3s,17-dihydroxypregnane-20-one which includes: treating (1) a17(20)-OXidO-3B,11a,20- triacyloxypregnane, wherein the acyloxy groupshave the formula AcO, Ac being the acyl radical of an hydrocarboncarboxylic acid containing from one to eight carbon atoms, inclusive, insolution in an organic solvent which is nonreactive under the conditionsof the reaction, with (2) a solution of an alkali metal hydroxide inamount not more than the theoretical amount required completely tohydrolyze the starting 17- (20) -oxido-3fi,11a,20-triacyloxypregnane,and 3) separating the thus-produced 11a-acyloxy-3p,17-dihydroxypregnane-20-one from the reaction product.

12. A process for the production of lla-acetoxy-3a,17-dihydroxypregnane-ZO-one which includes: treating (1)17(20)-oxido-3a,11a,20-triacetoxypregnane, in solution in ethanol, with(2) a solution containing approximately the theoretical amount of sodiumhydroxide for complete hydrolysis of the starting17(20)-oxido-3a,11a,20-triacetoxypregnane and (S) separating thethusproduced 11a-acetoxy-3a,17-dihydroxypregnane- 20-one from thereaction product.

13. A process for the production of-Ila-propionoxy-3a,17-dihydroxypregnane-20-one which includes: treating(1) 17(20)-0Xid0-3a,11a,20- tripropionoxypregnane, in solution inethanol, with (2) a solution containing approximately the theoreticalamount of sodium hydroxide for complete hydrolysis of the starting 17(20) -OXidO-3a,- 11(1,20-tripropionoxypregnane and (3) separating thethus-produced 11a-propionoxy-3a,17-dihydroxypregnane-ZO-one from thereaction product.

14. A process for the production of Ila-acetoxy-38,17-dihydroxypregnane-ZO-one which includes: treating (1)17(20)-oxido-3p,11,20-triacetoxypregnane, in solution in ethanol, with(2) a solution containing the theoretical amount of sodium hydroxide forcomplete hydrolysis of the

1. AN 11A-OXYGENATED-317-DIHYDROXYPREGNANE-20-ONE OF THE FORMULA: